CN108558758A - A kind of synthetic method of 4- fluorine isoquinolin -5- amine - Google Patents
A kind of synthetic method of 4- fluorine isoquinolin -5- amine Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The present invention provides a kind of synthetic methods of 4 fluorine isoquinolin, 5 amine.The synthetic method of the present invention, passed through as raw material using 1 alcohol of isoquinolin and 4 fluorine, 3 methoxyisoquinoliae, 1 alcohol is obtained by the reaction with Selectfluor, it is dissolved in HCl and 4 fluorine isoquinolin, 1 alcohol is obtained by the reaction, 1 chlorine, 4 fluorine isoquinolin is obtained with phosphorus oxychloride reaction, 4 fluorine isoquinolin are obtained under catalyst, 4 fluorine, 5 nitroisoquinoline is obtained by the reaction with concentrated nitric acid, finally iron powder reducing obtains 4 fluorine isoquinolin, 5 amine under acid conditions.The synthetic method of 4 fluorine isoquinolin, 5 amine of the present invention, route is succinct, rational technology, and cost of material is low, simple and easy to get, and operation and convenient post-treatment, total recovery is high, does not use poisonous reagent, is easy to amplify, can carry out the large-scale production of 4 fluorine isoquinolin, 5 amine.
Description
Technical field
The invention belongs to isoquinoline compound synthesis technical fields, are related to a kind of synthesis side of 4- fluorine isoquinolin -5- amine
Method.
Background technology
Isoquinoline compound is very important one kind compound in nitrogen heterocycles alkaloid, and there is significant physiology to live
Property and be widely applied foreground.It withers the study found that isoquinoline alkaloid can resist from alkylation, regulation, inhibition respectively
It dies gene, the different mechanisms such as new vessels generation is inhibited to play antitumor action.Currently, isoquinolin has played in drug
Huge effect, such as arcotic (quotane quinoline), antihypertensive drugs (quinapril hydrochloride), antifungal drug (1,2,3,4-
Tetrahydro quinazoline), vasodilator (papaverine) etc..Meanwhile isoquinoline compound can be used for manufacture dyestuff, paint,
Insecticide, preservative and disinfectant.In drug design process, fluorine atom is usually introduced, to improve small molecule drug effect, change it
Pharmacokinetic properties make it develop into clinical treatment drug, and about 15-20% has in the new drug listed every year
Therefore machine fluorine compounds improve its druggability in 4 introducing fluorine atoms of isoquinolin.Pass through the ammonia of 4- fluorine isoquinolin -5- amine
Base can generate a variety of different amides with the coupling of a variety of different carboxylic acids, and there is these amides very high potassium ion to reconcile work
Property, quantity and rate of the potassium ion by cell membrane can be reconciled.
Due to 4- fluorine isoquinolin -5- amine have so it is superior modify characteristic, organic synthesis circle especially
Pharmaceutical chemistry circle causes extensive concern.From 4- fluorine isoquinolin -5- amine, the molecule with specific structure is synthesized, then
The research that SAR is carried out by the structural modification of this molecule is obtaining the research and development of efficient drug candidate molecule also just with it
Orderly expansion also achieves very important achievement.
(application [J] the organic chemistry of fluorine atom in SARS drug design, 2011,31 (11) such as Wang Jiang, Liu Hong:
Application of the fluorine atom in SARS drug design 1785-1798) is had studied, the introducing of fluorine atom or fluoro-containing group can adjust medicine
The physicochemical characteristics of object small molecule changes the pharmacokinetics performance of small molecule, improves the bioavilability of drug.In addition,
Carbon-fluorine bond has stronger stability so that the metabolic stability of drug molecule increases, when extending the effect of drug in vivo
Between, therefore, carbon-fluorine bond may be used to the hydrocarbon site for being metabolized unstable and replace, the medicine of drug can be improved for power
Learn characteristic.But the activity of fluorine atom itself is very high, is difficult in the reaction control, especially introduces fluorine atom on location
When difficulty bigger, therefore, the preparation of organic fluorocompound is still the research field of a very challenging property.
Currently, the main method of 4- fluorine isoquinolin -5- amine synthesis is 4- fluorine isoquinolin with the concentrated sulfuric acid, potassium nitrate at -5 DEG C
The fluoro- 5- nitroisoquinolines of 4- are generated by nitration reaction, 4- fluorine is then obtained by reduction reaction with concentrated hydrochloric acid, stannous chloride again
Isoquinolin -5- amine.But raw material 4- fluorine isoquinolin prices are particularly expensive, the country lacks supplier.
Invention content
In view of the deficiencies of the prior art, one of the objects of the present invention is to provide a kind of synthesis of 4- fluorine isoquinolin -5- amine
Method,
For this purpose, the present invention uses following technical scheme：
A kind of synthetic method of 4- fluorine isoquinolin -5- amine, the synthetic method include the following steps：
1) acetonitrile, methanol are added into isoquinolin -1- alcohol, Selectfluor reagents, back flow reaction obtains the fluoro- 3- of 4-
Methoxyisoquinoliae -1- alcohol, wherein the molar ratio of the isoquinolin -1- alcohol and the methanol is 1:(2~3), the acetonitrile with
The volume ratio of the methanol is 1:The molar ratio of (1~1.5), the isoquinolin -1- alcohol and the Selectfluor reagents is
1:(1~3)；
2) the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- that step 1) obtains is dissolved in solvent, acid reaction is added, obtains 4- fluorine
Isoquinolin -1- alcohol；
3) phosphorus oxychloride is added portionwise in the 4- fluorine isoquinolin -1- alcohol obtained to step 2), and back flow reaction obtains the chloro- 4- of 1-
Fluorine isoquinolin；
4) the chloro- 4- fluorine isoquinolin of 1- that step 3) obtains is dissolved in solvent, catalyst is added, be passed through hydrogen reaction, obtain
4- fluorine isoquinolin；
5) the 4- fluorine isoquinolin obtained to step 4) is dissolved with solvent, and nitric acid reaction is added, it is different to obtain the fluoro- 5- nitros of 4-
Quinoline；
6) the fluoro- 5- nitroisoquinolines of 4- that step 5) obtains are dissolved with solvent, iron powder are added, is reacted under acid condition,
Obtain 4- fluorine isoquinolin -5- amine.
In step 1), the time of the reflux is 2~4h, such as the time of reflux is 2h, 2.5h, 3h, 3.5h, 4h.
In step 2), the solvent is ethyl acetate.
In step 2), the acid is hydrochloric acid.
Preferably, the molar ratio of the fluoro- 3- methoxyisoquinoliaes -1- alcohol of the 4- and the hydrochloric acid is (1~3):1, such as
The molar ratio of the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- and the hydrochloric acid is 1:1、1.5:1、2:1、2.5:1、 3:1.
In step 2), the temperature of the reaction is 30~50 DEG C, for example, reaction temperature is 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C,
50℃；The time of the reaction is 10~15h, such as the reaction time is 10h, 11h, 12h, 13h, 14h, 15h.
In step 3), the molar ratio of the 4- fluorine isoquinolin -1- alcohol and the phosphorus oxychloride is 1:(5~10), such as institute
The molar ratio for stating 4- fluorine isoquinolin -1- alcohol and the phosphorus oxychloride is 1:5、1:6、1:7、1:8、1:9、 1:10.
Preferably, in step 3), time of the back flow reaction is 2~5h, for example, back flow reaction time be 2h, 3h,
4h、5h。
In step 4), the solvent is the mixed liquor of the aqueous solution and methanol of alkali.
Preferably, the catalyst is Pd/C.
Preferably, the alkali is sodium hydroxide, lithium hydroxide or potassium hydroxide.Wherein alkali is generally excessive, and dosage is bigger
More be conducive to react.
Preferably, in step 4), the temperature of the reaction is 20~30 DEG C, for example, the temperature of reaction be 20 DEG C,
21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃、30℃；It is described
The time of reaction is 2~5h, such as the time of reaction is 2h, 3h, 4h, 5h.
In step 5), the solvent is sulfuric acid.
Preferably, in step 5), the reaction temperature be 20~30 DEG C, such as reaction temperature be 20 DEG C, 21 DEG C, 22
℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃、30℃；The time of the reaction be 2~5h, such as reaction when
Between be 2h, 3h, 4h, 5h.
Preferably, in step 6), the solvent is the mixed liquor of second alcohol and water.Preferably, in step 6), the ethyl alcohol with
The volume ratio of the water is 1:1.
Preferably, in step 6), the acid condition is acetic acid.
Preferably, in step 6), the reaction temperature be 60~90 DEG C, such as reaction temperature be 60 DEG C, 65 DEG C, 70 DEG C,
75℃、80℃、85℃、90℃；The time of the reaction is 2~5h, such as the time of reaction is 2h, 3h, 4h, 5h.
As the preferred embodiment of the present invention, the synthetic method of 4- fluorine isoquinolin -5- amine includes the following steps：
1) acetonitrile, methanol are added into isoquinolin -1- alcohol, Selectfluor reagents, 2~4h of back flow reaction obtains 4-
Fluoro- 3- methoxyisoquinoliaes -1- alcohol, wherein the molar ratio of the isoquinolin -1- alcohol and the methanol is 1:(2~3), it is described
The volume ratio of acetonitrile and the methanol is 1:(1~1.5), the isoquinolin -1- alcohol rub with the Selectfluor reagents
You are than being 1:(1~3)；
2) the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- that step 1) obtains is dissolved in ethyl acetate, hydrochloric acid 30~50 is added
10~15h is reacted at a temperature of DEG C, obtains 4- fluorine isoquinolin -1- alcohol, wherein the fluoro- 3- methoxyisoquinoliaes -1- alcohol of the 4- and institute
The molar ratio for stating hydrochloric acid is (1~3):1；
3) phosphorus oxychloride is added portionwise in the 4- fluorine isoquinolin -1- alcohol obtained to step 2), and 2~5h of back flow reaction obtains 1-
Chloro- 4- fluorine isoquinolin, wherein the molar ratio of the 4- fluorine isoquinolin -1- alcohol and the phosphorus oxychloride is 1:(5~10)；
4) the chloro- 4- fluorine isoquinolin of 1- that step 3) obtains is dissolved in methanol, Pd/C and alkali is added, be passed through hydrogen, 20~30
2~5h is reacted at a temperature of DEG C, obtains 4- fluorine isoquinolin；
5) sulfuric acid and nitric acid are added in the 4- fluorine isoquinolin obtained to step 4), reacts 2~5h at a temperature of 20~30 DEG C,
Obtain the fluoro- 5- nitroisoquinolines of 4-；
6) mixed liquor of iron powder, second alcohol and water is added in the fluoro- 5- nitroisoquinolines of 4- obtained step 5), vinegar is added
Acid reacts 2~5h at a temperature of 60~90 DEG C, obtains 4- fluorine isoquinolin -5- amine.
In the present invention, the synthesis technology of 4- fluorine isoquinolin -5- amine, be using isoquinolin -1- alcohol as raw material, by with
The fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- is obtained by the reaction in Selectfluor, and 4- fluorine isoquinolin-is obtained by the reaction in the HCl for being dissolved in 0.5N
1- alcohol and phosphorus oxychloride (POCl3) the chloro- 4- fluorine isoquinolin of 1- is obtained by the reaction, obtain 4- fluorine isoquinolin and dense under Pd/C catalysis
Nitric acid reaction obtains the fluoro- 5- nitroisoquinolines of 4-, and finally under AcOH existence conditions, iron powder reducing obtains 4- fluorine isoquinolin -5-
Amine；The reaction equation of the synthetic method of the present invention is as follows：
In above-mentioned technique, first step reaction is substitution reaction, and reactant is isoquinolin -1- alcohol, Selectfluor, instead
It is acetonitrile (MeCN) and methanol to answer solvent；Second step reaction is that de-methoxy reacts, and reactant is the fluoro- 3- methoxyl groups isoquinolines of 4-
Quinoline -1- alcohol, agents useful for same HCl, reaction dissolvent are ethyl acetate (EA)；Three-step reaction is chlorination reaction, reactant 4-
Fluorine isoquinolin -1- alcohol, agents useful for same are phosphorus oxychloride (POCl3)；Four-step reaction is catalytic hydrogenation reaction, reactant 1-
Chloro- 4- fluorine isoquinolin, agents useful for same Pd/C, reaction solution are methanol and NaOH, reaction condition H2Under the conditions of；5th step is anti-
Nitration reaction is should be, reactant is 4- fluorine isoquinolin, and agents useful for same is sulfuric acid and nitric acid；Six-step process is that iron powder reducing is anti-
It answers, reactant is the fluoro- 5- nitroisoquinolines of 4-, and agents useful for same is Fe powder, and reaction solution is to wait than ethyl alcohol (EtOH) and water, AcOH
It is reacted under existence condition.
The second object of the present invention is to provide a kind of 4- fluorine isoquinolin -5- that synthetic method as described above is prepared
Amine.
Compared with prior art, beneficial effects of the present invention are：
The synthetic method of the 4- fluorine isoquinolin -5- amine of the present invention, solves the problems, such as that expensive starting materials are rare in the prior art,
Provide it is a kind of using isoquinolin -1- alcohol as the synthetic method of raw material, synthetic route is succinct, and process choice is reasonable, and cost of material is low,
Raw material is simple and easy to get, and operation and convenient post-treatment, total recovery is high, and yield does not use poisonous reagent, be easy to amplify up to 80%,
It can carry out the large-scale production of 4- fluorine isoquinolin -5- amine.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.
Unless specific instructions, various raw materials of the invention are commercially available buys, or is prepared according to the conventional method of this field
It obtains.
Embodiment
The first step：The synthesis of the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4-
Isoquinolin -1- alcohol (14.5g, 0.1mol) is added to MeCN (100ml), MeOH (100ml), Selectfluor
(1.3eq), rear temperature rising reflux 3h, after reaction, vacuum are spin-dried for reaction solution, and crude product is directly thrown in next step.
Second step：The synthesis of 4- fluorine isoquinolin -1- alcohol
The fluoro- 3- methoxyisoquinoliaes -1- alcohol (0.1mol) of 4- are dissolved in 0.5NHCl.aq (100ml), EA (100ml), 40
It DEG C is stirred overnight, EA extractions, column chromatography obtains product (13g, 80%).
Third walks：The synthesis of the chloro- 4- fluorine isoquinolin of 1-
POCl3 (150ml), temperature rising reflux 3h is added portionwise in 4- fluorine isoquinolin -1- alcohol (33g, 0.2mol), is reacted
After, vacuum screws out extra POCl3, Na2CO3Aq. pH, EA extractions is adjusted to be spin-dried for column chromatography and obtain product (25g, 70%).
4th step：The synthesis of 4- fluorine isoquinolin
The chloro- 4- fluorine isoquinolin (10g) of 1- are dissolved in MeOH (100ml), and Pd/C, 10%NaOHaq. (1eq), H is added2Room temperature
3h is reacted, after reaction, low temperature screws out extra MeOH, and EA extracts to obtain product, directly throws in next step.
5th step：The synthesis of the fluoro- 5- nitroisoquinolines of 4-
50ml sulfuric acid is added in reaction bulb, T=0 DEG C is cooled to, 4- fluorine isoquinolin (29g, 0.2mmol) is added portionwise,
Nitric acid (1.3eq) is added dropwise again, is warmed to room temperature reaction 3h, reaction solution is added in ice cube, NaOHaq. tune pH=11, filtered,
Filter residue, which is washed with water, dries to obtain product 23g, directly throws in next step.
6th step：The synthesis of 4- fluorine isoquinolin -5- amine
Into 250ml there-necked flasks, EtOH100ml, H is added20100ml, AcOH (1eq), Fe (7eq), are heated to 80 DEG C,
It is carefully added into the fluoro- 5- nitroisoquinolines (19g, 0.1mol) of 4- in batches again, the reaction was continued 4h after adding after the reaction was complete, is filtered,
Filtrate is spin-dried for column chromatography and obtains product (12.8g, 80%).
1HNMR (400MHz, DMSO-d6), δ:8.94 (s, 1H), 8.20 (d, J=5.1Hz, 1H), 7.44 (t, J=
7.9Hz, 1H), 7.30 (dd, J=8.0,1.7Hz, 1H), 6.94 (d, J=7.7Hz, 1H), 5.95 (s, 2H).ESI+- MS, m/
z:163.1[M+H]+。
Comparative example 1
This comparative example compared with Example 1, the difference is that, in step 1), the volume ratio of acetonitrile and methanol is 1:5,
Other conditions are same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is 68%.
Comparative example 2
This comparative example compared with Example 1, the difference is that, in step 1), the volume ratio of acetonitrile and methanol is 1:
0.1, other conditions are same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is 71%.
Comparative example 3
This comparative example compared with Example 1, the difference is that, in step 2), the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4-
Molar ratio with hydrochloric acid is 6:1, other conditions are same as Example 1, this comparative example obtains the receipts of 4- fluorine isoquinolin -5- amine
Rate is 63%.
Comparative example 4
This comparative example compared with Example 1, the difference is that, in step 2), the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4-
Molar ratio with hydrochloric acid is 1:0.5, other conditions are same as Example 1, this comparative example obtains 4- fluorine isoquinolin -5- amine
Yield is 74%.
Comparative example 5
This comparative example compared with Example 1, the difference is that, in step 3), 4- fluorine isoquinolin -1- alcohol and phosphorus oxychloride
Molar ratio be 1:2, other conditions are same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is
70%.
Comparative example 6
This comparative example compared with Example 1, the difference is that, in step 3), 4- fluorine isoquinolin -1- alcohol and phosphorus oxychloride
Molar ratio be 3:1, other conditions are same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is
59%.
Comparative example 7
This comparative example compared with Example 1, the difference is that, in step 4), used catalyst is cesium carbonate, other
Part is same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is 42%.
Comparative example 8
This comparative example compared with Example 1, the difference is that, in step 6), reaction temperature is 40 DEG C, and the reaction time is
2h, other conditions are same as Example 1, and the yield that this comparative example obtains 4- fluorine isoquinolin -5- amine is 57%.
Raw material proportioning is too low or excessively high it can be seen from comparative example 1-7, the type of catalyst in feed change, final to make
The yield of the 4- fluorine isoquinolin -5- amine obtained is not high；In synthetic method it can be seen from comparative example 8, change reaction time and
Temperature equally affects the yield of 4- fluorine isoquinolin -5- amine.
The synthetic method of the 4- fluorine isoquinolin -5- amine of the present invention, synthetic route is succinct, and process choice is reasonable, cost of material
Low, raw material is simple and easy to get, and operation and convenient post-treatment, total recovery is high, and yield does not use poisonous reagent, be easy to put up to 80%
Greatly, the large-scale production of 4- fluorine isoquinolin -5- amine can be carried out.
The present invention illustrates detailed process equipment and the technological process of the present invention by above-described embodiment, but the present invention is not
It is confined to above-mentioned detailed process equipment and technological process, that is, does not mean that the present invention has to rely on above-mentioned detailed process equipment and work
Skill flow could be implemented.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to product of the present invention
The equivalence replacement of each raw material and the addition of auxiliary element, the selection of concrete mode etc., all fall within protection scope of the present invention and public affairs
Within the scope of opening.
Claims (10)
1. a kind of synthetic method of 4- fluorine isoquinolin -5- amine, which is characterized in that the synthetic method includes the following steps：
1）Acetonitrile, methanol are added into isoquinolin -1- alcohol, Selectfluor reagents, back flow reaction obtains the fluoro- 3- methoxyl groups of 4-
Isoquinolin -1- alcohol, wherein the molar ratio of the isoquinolin -1- alcohol and the methanol is 1:(2 ~ 3), the acetonitrile and the first
The volume ratio of alcohol is 1:The molar ratio of (1 ~ 1.5), the isoquinolin -1- alcohol and the Selectfluor reagents is 1:(1~3)；
2）By step 1）The obtained fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- is dissolved in solvent, and acid reaction is added, obtains 4- fluorine isoquinolines
Quinoline -1- alcohol；
3）To step 2）Phosphorus oxychloride is added portionwise in obtained 4- fluorine isoquinolin -1- alcohol, and it is different to obtain the chloro- 4- fluorine of 1- for back flow reaction
Quinoline；
4）By step 3）The obtained chloro- 4- fluorine isoquinolin of 1- is dissolved in solvent, and catalyst is added, and is passed through hydrogen reaction, obtains 4- fluorine
Isoquinolin；
5）To step 4）Obtained 4- fluorine isoquinolin is dissolved with solvent, and nitric acid reaction is added, obtains the fluoro- 5- nitroisoquinolines of 4-；
6）By step 5）The obtained fluoro- 5- nitroisoquinolines of 4- are dissolved with solvent, and iron powder is added, reacts, obtains under acid condition
4- fluorine isoquinolin -5- amine.
2. synthetic method according to claim 1, which is characterized in that step 1）In, the time of the reflux is 2 ~ 4h.
3. synthetic method according to claim 1 or 2, which is characterized in that step 2）In, the solvent is ethyl acetate.
4. according to the synthetic method described in one of claim 1-3, which is characterized in that step 2）In, the acid is hydrochloric acid；
Preferably, the molar ratio of the fluoro- 3- methoxyisoquinoliaes -1- alcohol of the 4- and the hydrochloric acid is (1 ~ 3):1.
5. according to the synthetic method described in one of claim 1-4, which is characterized in that step 2）In, the temperature of the reaction is
30 ~ 50 DEG C, the time of the reaction is 10 ~ 15h.
6. according to the synthetic method described in one of claim 1-5, which is characterized in that step 3）In, the 4- fluorine isoquinolin -1-
The molar ratio of alcohol and the phosphorus oxychloride is 1:(5~10)；
Preferably, step 3）In, the time of the back flow reaction is 2 ~ 5h.
7. according to the synthetic method described in one of claim 1-6, which is characterized in that step 4）In, the solvent is the water of alkali
The mixed liquor of solution and methanol；
Preferably, the catalyst is Pd/C；
Preferably, the alkali is sodium hydroxide, lithium hydroxide or potassium hydroxide；
Preferably, step 4）In, the temperature of the reaction is 20 ~ 30 DEG C, and the time of the reaction is 2 ~ 5h.
8. according to the synthetic method described in one of claim 1-7, which is characterized in that step 5）In, the solvent is sulfuric acid；
Preferably, step 5）In, the reaction temperature is 20 ~ 30 DEG C, and the time of the reaction is 2 ~ 5h；
Preferably, step 6）In, the solvent is the mixed liquor of second alcohol and water；
Preferably, step 6）In, the volume ratio of the ethyl alcohol and the water is 1:1；
Preferably, step 6）In, the acid condition is acetic acid；
Preferably, step 6）In, the reaction temperature is 60 ~ 90 DEG C, and the time of the reaction is 2 ~ 5h.
9. according to the synthetic method described in one of claim 1-8, which is characterized in that the synthetic method includes the following steps：
1）Acetonitrile, methanol are added into isoquinolin -1- alcohol, Selectfluor reagents, 2 ~ 4h of back flow reaction obtains the fluoro- 3- first of 4-
Oxygroup isoquinolin -1- alcohol, wherein the molar ratio of the isoquinolin -1- alcohol and the methanol is 1:(2 ~ 3), the acetonitrile and institute
The volume ratio for stating methanol is 1:The molar ratio of (1 ~ 1.5), the isoquinolin -1- alcohol and the Selectfluor reagents is 1:(1~
3)；
2）By step 1）The obtained fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- is dissolved in ethyl acetate, and 30 ~ 50 DEG C of temperature of hydrochloric acid are added
10 ~ 15h of lower reaction obtains 4- fluorine isoquinolin -1- alcohol, wherein the fluoro- 3- methoxyisoquinoliaes -1- alcohol of 4- and the hydrochloric acid
Molar ratio be (1 ~ 3):1；
3）To step 2）Phosphorus oxychloride is added portionwise in obtained 4- fluorine isoquinolin -1- alcohol, and 2 ~ 5h of back flow reaction obtains the chloro- 4- of 1-
Fluorine isoquinolin, wherein the molar ratio of the 4- fluorine isoquinolin -1- alcohol and the phosphorus oxychloride is 1:(5~10)；
4）By step 3）The obtained chloro- 4- fluorine isoquinolin of 1- is dissolved in methanol, and Pd/C and alkali is added, is passed through hydrogen, 20 ~ 30 DEG C of temperature
2 ~ 5h of lower reaction, obtains 4- fluorine isoquinolin；
5）To step 4）Sulfuric acid and nitric acid are added in obtained 4- fluorine isoquinolin, reacts 2 ~ 5h at a temperature of 20 ~ 30 DEG C, obtains 4-
Fluoro- 5- nitroisoquinolines；
6）By step 5）The mixed liquor of addition iron powder, second alcohol and water in the obtained fluoro- 5- nitroisoquinolines of 4-, addition acetic acid, 60 ~
2 ~ 5h is reacted at a temperature of 90 DEG C, obtains 4- fluorine isoquinolin -5- amine.
10. a kind of 4- fluorine isoquinolin -5- amine being prepared such as claim 1-9 any one of them synthetic methods.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110156760A (en) * | 2019-05-17 | 2019-08-23 | 济南大学 | A kind of preparation method of 4- (1,4- dioxane -2- base) quinoline -2- methyl formate derivative |
| CN112047884A (en) * | 2020-09-11 | 2020-12-08 | 沈阳市摩尔医药技术开发有限责任公司 | Synthesis method of 4-fluoroisoquinoline sulfate |
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| CN110156760B (en) * | 2019-05-17 | 2022-09-30 | 济南大学 | Preparation method of 4- (1, 4-dioxane-2-yl) quinoline-2-methyl formate derivative |
| CN112047884A (en) * | 2020-09-11 | 2020-12-08 | 沈阳市摩尔医药技术开发有限责任公司 | Synthesis method of 4-fluoroisoquinoline sulfate |
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